Enteric coating, comprising alginic acid, for an oral preparation

ABSTRACT

A composition for forming an enteric coating on a tablet, capsule or pellet for oral ingestion includes a liquid mixture of alginic acid particles dispersed in an aqueous solution of a binding agent of locust bean, gum, gelatine, vegetable hydrocolloids and/or animal protein.

This application is a U.S. national phase filing of PCT/DK97/00252,filed Jun. 6, 1997, which claimed priority of Danish Application0636/96, filed Jun. 6, 1996.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a composition for forming an entericcoating on an oral preparation, such as a preparation in the form oftablets, capsules, or pellets.

2. The Prior Art

Enteric coatings are taken to mean coatings which, among other things,serve to prevent an undesired influence upon the active substancecontained in the oral preparation in the stomach.

Enteric coatings are for example used for

(1) preventing the gastric juice from reacting with or destroying theactive substance,

(2) preventing dilution of the active substance before it reaches theintestine,

(3) ensuring that the active substance is not released until after thepreparation has passed the stomach, and

(4) preventing live bacteria contained in the preparation from beingkilled because of the low pH-value in the stomach.

Enteric coatings can also be used for avoiding irritation of or damageto the mucous membrane of the stomach caused by substances contained inthe oral preparation, and for counteracting or preventing formation orrelease of substances having an unpleasant odor or taste in the stomach.Finally, such coatings can be used for preventing nausea or vomiting onintake of oral preparations.

It is known to prepare enteric coatings from one or more layers of fattyacids, such as stearic acid and palmitic acid, wax, shellac and/orcellulose acetate phthalate.

It is an essential disadvantage of the known enteric coatingcompositions that use of organic solvents in the form of acetone orchlorine containing compounds is required for their formation.

As regards cellulose acetate phthalates, it further applies that theymust not be used for coating foodstuffs and food supplements, as theyare not approved for use in foodstuffs in the EU, cf. “Fortegnoise overtilsentningsstoffer til levnedsmidier”, Positivlistein,Levnedemiddelstyrelsen, December 1995, Publ. No. 231, ISSN 0903-9733,ISSN 0108-1667.

Another known enteric coating composition is acrylic resin which isavailable in commerce under the trade mark Eudragit®, but this coatingcomposition also is not generally approved for formation of coatings onfoodstuffs or food supplements.

JP patent publication No. 05-32543 discloses enteric coated capsuleseach consisting of a body and a cap containing a drug, said body and capcomprising a particulate matter such as alginic acid dispersed in anagar containing base material. The body and cap are prepared by heatingan aqueous mixture of particulate material and agar containing materialto about 100° C., cooling said mixture and converting the mixture intocapsules by moulding.

U.S. Pat. No. 4,661,162 discloses an enteric soluble compositioncomprising an enteric-soluble polymer, such ascarboxymethylethylcellulose, in admixture with a polyanionic polymer,such as algaric acid, which is soluble in or permeable to liquids havinga pH value less than or equal to 2.

SUMMARY OF THE INVENTION

It has now surprisingly been found that a known substance, alginic acid,which has been approved for use as additive for foodstuffs, is usefulfor forming effective enteric coatings on oral preparations when it iscombined with a binding agent.

The coating composition of the invention is characterized in that itcomprises a liquid mixture of a major amount of alginic acid particlesdispersed in an aqueous solution of a minor amount of a water solublebinding agent which is approved for use for coating foodstuffs and/orfood supplements.

Thus, it has turned out that by forming a layer of a liquid mixture ofalginic acid particles and the above-mentioned binding agent on apreparation of the form of tablets, capsules, pellets and the like, acoating is obtained which is resistant to influence of gastric juice,and which dissolves under neutral or basic conditions. This is due tothe fact that alginic acid is insoluble in acids and soluble in basic orneutral media and hereby in a manner known per se forms alginate.

The best protective effect is obtained when the alginic acid particlesin the mixture of alginic acid and binding agent have an averageparticle size of maximally 2 μm, but depending on the kind of thepreparation to be provided with an enteric coating, larger and smallerparticles can be used.

A particularly good protective effect is obtained by using a mixture ofalginic acid particles with varying particles sizes.

As binding agent for the alginic acid particles, a wide variety oftherapeutic and/or nutritionally acceptable binding agents can beemployed. Preferred binding agents useful in connection with drugs aswell as foodstuffs and food supplements, include locust bean gum,gelatine, vegetable hydrocolloids and animal proteins.

The liquid mixture of alginic acid particles and binding agent isaqueous, and the water preferably makes up more than 95% of the weightof the mixture. The ratio of alginic acid to binding agent may varywithin wide limits depending on the binding agent, the particles size ofthe alginic acid, and the field of application of the coatingcomposition.

Typically, alginic acid and binding agent are used in a weight ratio ofup to 4:1.

When using an aqueous mixture of alginic agent and binding agent, suchas locust bean gum, the latter is preferably dissolved in a portion ofthe water, and the alginic acid is slurried in the remaining portion ofthe water, whereafter the slurry is optionally subjected to a treatment,e.g. in a homogenizer, in order to obtain the desired particle size.Finally, the two fractions are mixed, and optionally a furtherhomogenization is performed in order to distribute the alginic acid inthe firstmentioned fraction.

The liquid mixture of alginic acid and binding agent may also containvarious additives. For example, softening agent in the form of an oil,such as olive oil, and detackifiers, such as magnesium stearate, andfats may be used.

The formation of an enteric coating on an oral preparation using thecoating composition according to the invention can take place in amanner known per se, e.g., by direct spraying of the liquid mixture ofalginic acid and binding agent on the preparation in a fluid bed or acoating pan.

The invention also concerns a preparation provided with an entericcoating prepared by using the coating composition according to theinvention.

Oral preparations which are coated with enteric coating according to thepresent invention are particularly suitable for containing liveorganisms, such as freeze-dried bacteria.

Further, the invention relates to a process for the preparation of anenteric coating on an oral preparation containing live organisms, whichprocess does not employ toxic organic solvents, and in which thetemperature does not exceed about 30° C.

When coating an oral preparation containing live organisms, e.g.freeze-dried bacteria, it is important that the bacteria are not exposedto extraneous influences which may entail that the bacteria are damagedor at worst die.

Use of toxic organic solvents and high temperatures in the preparationof enteric coatings on the oral preparation should consequently beavoided. In the present invention for the preparation of entericcoatings on the oral preparation, the temperature preferably does notexceed about 30° C. Further, no toxic organic solvents are used.

In a further embodiment of the process according to the presentinvention, the oral preparation which is coated with the enteric coatingis constituted by capsules, preferably gelatine capsules. If apreparation in the form of capsules is used, also a gentle preparationof the active substance is obtained prior to it being coated with theenteric coating, as the physical conditions during the preparation ofthe capsules do not influence the active substance. The activesubstance, e.g. in the form of freeze-dried bacteria, is filled intoempty capsules, as opposed to tablets and pellets where the activesubstance participates in the preparation of the tablet or pellet.

The enteric coating has turned out to be particularly effective forcapsules of gelatine.

Depending on the kind of the preparation, it may be desirable to buildthe enteric coating from several layers, one of which is constituted byfine grained alginic acid particles bonded by a binding agent.

For example, it may be desirable to prepare a coating consisting of fourlayers, where one of the centre layers is prepared from the coatingcomposition according to the invention.

It may also be desirable to provide an inner layer consisting of severalsub-layers. Similarly, the outer layer may be built from several layers.

In the following the invention is described in more detail, referencebeing made to the following example.

EXAMPLE

For use in the preparation of an enteric coating on gelatine capsulescontaining freeze-dried lactic acid bacteria, the following threecoating compositions are employed:

Coating composition 1 Zein F-4000 10% Ethyl alcohol 96% 79% Purifiedwater  9% Magnesium stearate  2%

Coating composition 1 was prepared by slurrying Zein F-4000 in ethylalcohol, whereafter the magnesium stearate was admixed. Finally, thewater was admixed with stirring.

Coating composition 2 Sodium alginate  2.7% Purified water   97% Oliveoil 0.15% Magnesium stearate 0.15%

Coating composition 2 was prepared by dissolving sodium alginate in thewater, whereafter the olive oil and the magnesium stearate were addedand homogenized by means of a homogenizer.

Coating composition 3 Alginic acid 1.5% Locust bean gum 0.8% Olive oil0.8% Purified water 96.9% 

Coating composition 3 was prepared by dissolving 0.8 parts of locustbeam gum in 38.4 parts of water, whereafter 0.8 parts of olive oil wereadded, and the mixture was emulsified with a homogenizer. 1.5 parts ofalginic acid were slurried in 58 parts of water and homogenized with ahomogenizer, whereafter the above olive oil emulsion was added, and themixture was homogenized with a homogenizer.

The coating compositions used were applied onto the gelatine capsules inthe order and under the conditions stated in Table 1 below.

TABLE 1 Coating Amount of Nozzle Nozzle Spray Starting Post-dryingPost-drying Water activity in Process composition liquid, g diameterpressure speed temperature min. min. capsule Preheating 0   0 30° C. for15 min. 0.198 before process Pretreatment Ethanol 96% 1500 g 0.8 mm 0,8bar 60 g/min. 30° C. 30° C. 0 0.162 after process 1st 1 5000 0.8 mm 0.8bar 60 g/min. 30° C. 30° C. 15 min. 0.218 after process Layer 2 5000 1.2mm 60 g/min. 2nd Layer 3 5000 1.2 mm 0.8 60 g/min. 30° C. 30° C. 10 min.0.218 after process 3rd 1 1000 0.8 mm 0.8 bar 60 g/min. 30° C. 30° C. 0Layer 2 1000 1.2 mm 60 g/min. 4th Layer 1  700 0.8 mm 0.8 bar 60 g/min.30° C. 30° C. 15 min. Cooling 0 up to 22° C. - heat up to 22° C. 0.209after process

As appears from the table above, the water activity in the capsules(measured by means of a “Novasina”-moisture meter) does not increasesignificantly in spite of aqueous coating compositions having been used.This is very important for the stability of many substances and for thesurvival of freeze-dried bacteria.

The finished capsules were tested in accordance with EuropeanPharmacepoeia: 6 capsules are exposed to the influence of 0.1Nhydrochloric acid at 37° C. for 2 hours in European Pharmacepoeia'sdecay apparatus and must show no signs of dissolution or disruptionwhich allows the content to escape. Thereafter, the acid is replaced bya phosphate buffer solution with pH 6.8. After 60 min, the capsules musthave dissolved.

The film coated capsules stood up to this test and had all dissolvedafter 18 min in the phosphate buffer.

For the purpose of clarifying the stability of lactic acid bacteriacontaining preparations provided with an enteric coating according tothe invention, decay experiments were performed in which the number ofmicro-organisms contained in enterically coated capsules were counted,before and after treatment with 0.1N HCl for 2 hours, and at 36-38° C.in accordance with Ph. Eur. 2nd Ed., 478, 1990.

The results of these decay experiments appear from Tables 2-5.

TABLE 2 Number of live lactobacillus pr. gram of Sample No. MRS agar 37°C.-3 days, CO₂-atomosphere 1 a 7.0 × 10⁷ 1 b 5.8 × 10⁷ Mean value: 6.8 ×10⁷ 2 a 7.3 × 10⁷ 2 b 6.9 × 10⁷

TABLE 3 Number of live bifidobacteria pr. gram Sample No. of RCM agar37° C.-5 days, anaerobic 1 a 4.0 × 10⁸ 1 b 3.9 × 10⁸ Mean value: 4.0 ×10⁸ 2 a 3.8 × 10⁸ 2 b 4.4 × 10⁸

TABLE 4 Number of live lactobacillus pr. gram of Sample No. MRS agar 37°C.-3 days, CO₂-atmosphere 1 a 2.0 × 10⁷ 1 b 1.4 × 10⁷ Mean value: 2.7 ×10⁷ 2 a 3.0 × 10⁷ 2 b 4.5 × 10⁷

TABLE 5 Number of live bifidobacteria pr. gram of Sample No. RCM agar37° C.-5 days, anaerobic 1 a 1.7 × 10⁷ 1 b 1.5 × 10⁷ Mean value: 2.0 ×10⁷ 2 d 2.2 × 10⁷ 2 b 2.5 × 10⁷

As appears from the above results, the acid treatment only results in anegligible drop in live micro-organisms.

What is claimed is:
 1. A composition for formation of an enteric coatingon an oral preparation, comprising a liquid mixture of alginic acidparticles dispersed in an aqueous solution of a water soluble bindingagent selected from the group consisting of locust bean, gum, gelatine,vegetable hydrocolloids and animal proteins, said liquid mixturecontaining a larger amount of alginic acid particles than water solublebinding agent.
 2. A composition according to claim 1, characterized inthat the alginic acid particles have an average particle size of 2 μm.3. A composition according to claim 1, wherein the alginic acidparticles have varying particle sizes.
 4. A composition according toclaim 1, wherein the alginic acid particles and the binding agent arepresent in a weight ratio of up to 4:1.
 5. A process of preparing acoated oral preparation, comprising spraying the oral preparation with acoating composition according to claim 1 and allowing the water toevaporate.
 6. A process according to claim 5, wherein the oralpreparation contains live bacteria.
 7. A process according to claim 5,wherein the oral preparation is in the form of capsules.
 8. A processaccording to claim 7, wherein said oral preparation is in the form of agelatine capsule.
 9. An oral preparation provided with an entericcoating, proposed from a liquid mixture of alginic acid particlesdispersed in an aqueous solution of a water soluble binding agentselected from the group consisting of locust bean, gum, gelatine,vegetable hydrocolloids and animal proteins, said liquid mixturecontaining a larger amount of alginic acid particles than water solublebinding agent.
 10. An oral preparation according to claim 9, furtherincluding live bacteria.
 11. An oral preparation according to claim 10,wherein said live bacteria are freeze dried.
 12. An oral preparationaccording to claim 9, in the form of tablets, capsules or pellets. 13.An oral preparation according to claim 12, wherein said oral preparationis in a gelatine capsule.
 14. An enterically coated oral preparationcomprising alginic acid particles dispersed in a matrix of awater-soluble binding agent selected from the group consisting oflocust, bean, gum, gelatine, vegetable hydrocolloids, and animalproteins, said liquid mixture containing a larger amount of alginic acidparticles than water soluble binding agent.